Why is thinking too much tiring? An experiment seeks the answer in glutamate

On September 10, 1984, one of the most exciting chess world championships in history began. The 21-year-old Garri Kasparov and Anatoli Karpov, 10 years older and champion for a decade, faced each other. After an overwhelming start of four wins for the latter and five draws (the championship was the best of six), the former forced 17 new draws in a row, winning his first game in game 32. After another series of draws, the challenger took the win on 47 and 48. On February 9, 1985, five months after the start of the championship and with a 5-3 result for Karpov, the president of the International Chess Federation, Florencio Campomanes, ended the tournament without a winner in a decision that generated much controversy at the time. Campomanes argued the decision on the mental fatigue of the players and their physical deterioration. It was the beginning of a two-decade rivalry between the two chess players that went beyond the sporting aspect. But a question remained in the air: why does thinking too much tire one so much?

A group of researchers from French universities has now come up with an answer: mental tasks that require greater effort would generate an extra accumulation and diffusion of molecules that are essential for good brain function, but which, in excess, are neurotoxic. To avoid this, the brain would command us to stop, creating the sensation of exhaustion. The idea is, although very suggestive, only a hypothesis yet to be demonstrated by other neuroscientists.

What the Gallic scientists did to study why mental exercise is as tiring as physical exercise was to recruit about fifty people to perform a series of tasks for 6.5 hours (the average working day in France). But while one group performed more complex tasks (essentially remembering a greater number and combinations of uppercase and lowercase letters in different colors that appeared on the computer screen), the demands on the other group were much less demanding. During the experiment, the participant’s brains were studied inside and out.

Thus, they carried out an eye-tracking system to record the greater or lesser dilation of the pupil. Previous research has observed that eye movement stops and dilates when performing a calculation or in the final phase of decision making. In addition, they used a brain imaging technique (magnetic resonance spectroscopy) to measure activity in the prefrontal cortex, the so-called executive brain, and the residuals it left behind. They also conducted performance tests and questionnaires on the subjective level of burnout.

“Glutamate is the main excitatory neurotransmitter in the brain, involved in many regions and in its regular functioning. What we observed is an increase with demanding tasks.”

The results of all these tests, published in the scientific journal Current Biology, show clear differences between the group that had to think less and those whose mental effort was greater. Thus, they saw signs of fatigue, including a reduction in pupil dilation, only in the second group. They also observed that, as the hours of work passed, the participants with more complex tasks ended up asking for more immediate rewards (what they were given for performing them). But the most definitive element for them is what they saw happening inside their heads. Those in this second group have higher levels of a molecule, glutamate, in the synapses (the electrochemical connection between nerve endings) of the lateral prefrontal cortex, which is responsible for cognitive control.

Antonius Wiehler is a researcher at the Paris Brain Institute, Pitié-Salpêtrière University Hospital, and co-author of this study. “Glutamate is the main excitatory [activation of synapses] neurotransmitter in the brain, involved in many regions and in its regular functioning. What we observed is an increase with demanding tasks: continuous work on tasks that require a high level of cognitive control lead to an increase in diffusion (spontaneous movement of molecules),” he explains in an email. Glutamate molecules are released in the brief space between the end of one neuron and the start of another, the synaptic cleft, where the exchange of information takes place and is essential to the process. Wiehler adds that, then, “brain activity in this region is down-regulated to avoid further accumulation of glutamate”. This is the moment when the brain says it is tired.

For the authors of the study, the increased presence of glutamate, together with the other observed changes, would support the idea that the accumulation of this molecule makes the additional activation of the prefrontal cortex more costly so that cognitive control is more difficult after a hard day of mental work.

The proposal of these scientists differs from the dominant ideas about mental fatigue, in particular from the group of depletion theories. In a simile with physical exercise and its energy consumption, their postulants argue that cognitive control (what to do, how and when or what not to do) incurs energy expenditure and when resources are depleted mental fatigue would appear. But it has not been demonstrated what energy is depleted (blood glucose, for example, has been suggested). Moreover, these proposals leave even more questions: Why does playing chess tire and seeing or hearing, which also requires conscious brain work for processing, not exhaust it?

“Our findings show that cognitive work results in the accumulation of harmful substance.”

For other psychologists and neuroscientists, brain fatigue would be an illusion generated by this organ as a warning system, like the burning of the skin is an illusion of the danger of fire. Mathias Pessiglione, Wiehler’s colleague at the Parisian university hospital and co-author of the study, comments on these positions: “Some influential theories have proposed that fatigue is a kind of illusion invented by the brain to make us stop what we are doing and move on to a more rewarding activity”. However, he adds in a note, “our findings show that cognitive work results in a real functional alteration, the accumulation of harmful substances, so fatigue would be a signal that makes us stop working, but with a different purpose: to preserve the integrity of brain functioning”.

The head of the neurology service of the Albacete University Hospital, Tomás Segura, is studying persistent covid sufferers who report mental fog and fatigue. “In general, fatigue as a medical term refers to the sensation of shortness of breath linked to exercise or heart failure. That’s why we say that in post-coronavirus syndrome there are many patients who have non-respiratory, non-cardiac fatigue. In that sense we can call it neurological, cognitive or mental fatigue,” Segura explains. What they have observed in these long-term coronavirus sufferers is fatigue similar to that caused by intensive cognitive tasks.

“Just to think that you have to go downstairs to buy bread, and it’s not that you lack the breath to do it, but just by thinking about the motor act, you are already tired. This has a lot to do with those areas of the brain where actions are planned and with the need for all glutamatergic transmission to function well in order to be activated,” says Segura and adds, “glutamate, which is one of the villains pointed out in the generation of brain damage in stroke, is also implicated, in this case, due to its deficiency, in certain neurodegenerative diseases and also in the explanation of the so-called neurological fatigue”.

Javier De Felipe, from the Cajal Laboratory of Cortical Circuits at the Polytechnic University of Madrid, considers the work of his French colleagues very suggestive and timely but believes that they go too far. “They pose the question very well, why thinking tires, but their answer is only a hypothesis,” he says. For him, they do not demonstrate the causal relationship between glutamate accumulation and mental fatigue. “Cognitive control is centered in the prefrontal cortex, but this area is hyperconnected with other areas of the brain. Why does glutamate accumulate in some areas and not others?

Leontxo García has been the chess specialist of El País since 1985, the year in which the longest series of games in history ended and he was present at the beginning of the second chapter of that story. “Karpov started winning 5-0 and was obsessed with making it 6-0 to cause Kasparov a psychological trauma from which he could never recover. So instead of taking risks to win a game, even if he lost a few along the way, he played very conservatively, waiting for Kasparov to make a mistake. But Kasparov, twelve years younger and much stronger physically, realized that his only trump card was to win by exhausting Karpov,” he recalls. Both had godfathers in the highest echelons of the former Soviet Union. “The godfathers of both were afraid that their man would lose; those of Karpov, because he was showing clear signs of exhaustion; those of Kasparov, because a single defeat was enough. So Campomanes decided to suspend the duel without a winner and resume it eight months later with the score 0-0″, García concludes. Campomanes prevented knowing if Kasparov, and mental fatigue, would have defeated Karpov.

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